FDA Advisory Committee Recommends Cardiovascular Safety Studies for Diabetes Drugs

July 03, 2008

July 3, 2008 — New diabetes drugs should be subjected to studies to rule out cardiovascular risk, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee decided at a meeting this week. But the specifics of what exactly those studies should involve were left open. Such safety information should also be sought for drugs already on the market, if possible, it was suggested.

The committee met on July 1 and 2 to discuss whether long-term cardiovascular safety data should be required for new and existing diabetes drugs. This discussion was deemed necessary because concerns about cardiovascular safety have been raised about several drugs in this field (rosiglitazone [Avandia, GlaxoSmithKline] and muraglitazar being recent examples), compounded by the recent results of the ACCORD trial, showing an increased mortality in patients undergoing intensive glucose lowering with multiple diabetes drugs.

FDA official Dr Mary Parks explained to the press after the meeting: "There have been calls for cardiovascular-outcome trials on diabetes drugs. But it was unclear to the FDA what exactly this meant." For example, she said the agency wanted to clarify whether these trials would need to rule out harm or to show cardiovascular benefit and whether the data would need to be in before or after approval. These questions and other specifics of how such trials should be conducted were therefore discussed by the advisory committee over the past two days.

Vote of 14-2 in Favor of Long-Term Trial

After a lengthy discussion on how the question to be voted on should be worded, the committee eventually settled on: "We are assuming that a drug/biologic with a safety signal in phase 2/3 trials will have to have an additional safety trial. But for those drugs without such a signal, should there be a requirement to conduct a long-term trial or provide equivalent evidence to rule out an unacceptable cardiovascular risk?" And they voted 14-2 in favor of this concept, with two abstentions.

The committee grappled with many other questions regarding specific issues such as whether these cardiovascular assessments should occur pre- or postapproval and design considerations such as what magnitude of increased cardiovascular risk should be ruled out, what the primary end point should be, what type of patient population should be enrolled, which treatment comparator(s) should be used, how deteriorating glycemic control should be handled, and how other cardiovascular risk factors should be managed.

That is one of the things that went wrong with rosiglitazone--they never conducted the trial that they had committed to at the time of approval.

While no firm consensus was reached on many of these issues, there was agreement on some points. Acting chair of the committee, Dr Kenneth Burman (Washington Hospital Center, Washington, DC), said: "I think we have consensus that we need either one large trial or a series of smaller trials to give information on cardiovascular risk. We don't need to show cardiovascular benefit given that these drugs already have a benefit in lowering blood glucose levels, which is known to be associated with a reduction in microvascular complications. But we do need to show lack of hazard." He added: "In my view, it is not possible to specify one size or duration of trial for all drugs. This would depend on what adverse events had already shown up in the development program and what other benefits the new drug was offering."

Virtually everyone on the panel agreed that the primary end point should be a composite of hard end points (preferably CV death/MI/stroke). Many members suggested a duration of at least three to five years would be required and that the population involved should be mainly diabetics at high risk of heart disease to ensure enough events.

There was also consensus that such a trial should evaluate the new drug vs an active comparator, but this was problematic in that no diabetes drug currently on the market was known definitely to be free of cardiovascular risk. Most committee members suggested metformin as the best comparator to start with, as this drug had the most evidence of cardiovascular safety/benefit.

It was agreed that deteriorating glycemic control and other cardiovascular risk factors (such as cholesterol and blood pressure) had to be managed in both arms of the trial, although they were confounders. Some panel members suggested that the goals for these risk factors should be stated but it should not be insisted upon that they be met, as there should be some room to show effects of the new drug on these risk factors. On this issue, panel member Dr Marvin Konstam (Tufts-New England Medical Center, Boston, MA) said: "We need to try to ensure that if a drug has a favorable effect on LDL we want that to show up, and that won't happen if all patients have their LDL treated to target."

There was also extensive discussion on whether the cardiovascular-outcome data needed to be available pre- or postapproval and how this could be achieved in the most timely and least burdensome manner, so not to delay too much the time taken for a drug to reach the market.

Preapproval Screening Trial Followed by Larger Trial Postapproval?

In a presentation on the first day of the meeting, Dr Steven Nissen (Cleveland Clinic, OH) suggested that two separate trials be conducted--a preapproval screening trial to rule out a large cardiovascular risk, followed by a large randomized trial to estimate cardiovascular risk more accurately, which must be under way as a condition of approval but could be completed after approval. "This would provide more reliable preapproval data but only delay approval by a few months and would also ensure that solid data would be generated for all new drugs," Nissen said.

He added that it was essential that the large trial was under way before approval was granted, as once a drug was approved, promises by sponsors to do further trials are often not kept. "Only 14% of phase 4 commitments actually get done. That is one of the things that went wrong with rosiglitazone--they never conducted the trial that they had committed to at the time of approval. I think we have to learn from those mistakes."

Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) then gave a talk on the best way to perform large randomized trials to get answers on cardiovascular safety as quickly and inexpensively as possible, basically emphasizing the need to focus on major adverse events and not to get bogged down on minor adverse events and bureaucracy.

The second day of the meeting was taken up discussing Nissen's idea or variations of it. The suggestion was raised that one large trial could be conducted, which would be started preapproval, and that an interim analysis after a specific number of events had been reported could be used to gain an idea of safety for approval, with the trial continuing after approval to give a better safety estimate. Many panel members seemed to like this idea. Some voiced the suggestion that the trial may be able to be stopped if there were no obvious risk at further interim analyses.

But Nissen told heartwire he did not like the idea of doing one study and taking a look at the interim results for approval. "Once you take a look you have affected the behavior in the trial. And my own view is that is not desirable," he said.

Some panel members also suggested that if the preapproval screening trial showed a benefit, a larger trial may not be necessary, but others disagreed, pointing out that a large trial was the only way to know for sure what the cardiovascular safety profile was. Nissen was also adamant that a long-term trial had to be conducted, even if the preapproval screening trial was suggesting a cardiovascular benefit. "If the preapproval trial suggested benefit, that trial will still have very wide confidence intervals because it will not be big enough to show a definitive result. It will simply reduce the uncertainty. And if you really want to do this correctly, you have to nail down the full answer in a large outcomes trial," he commented to heartwire after the meeting.

At What Level Will the Bar Be Set?

A long time at the meeting was spent discussing statistical issues of how many events would be needed in a preapproval trial to rule out a large hazard and what the level of hazard ruled out at this stage needs to be set at. No definite consensus was reached on these issues, although one suggestion was for a screening trial to have 125 events, which could rule out an upper confidence interval of harm of 1.8 (corresponding to a point estimate of 1.26).

Konstam commented: "I don't feel we as a panel should specify any specific upper boundary. I would rather see a clinical assessment of risk. Whatever the statistical bound of a trial is, my interpretation of that trial will be determined by other things--the point estimate, the number of events, whether there are other signals of concern, the incremental value of the drug. If the drug can achieve better glycemic control with reduced risk of hypoglycemia, I may be more accepting of a higher upper boundary on cardiovascular risk. And this may be different for a completely new class of drug rather than another drug in an established class."

What Now?

FDA official Dr John Jenkins told the postmeeting press conference that the agency now needs to digest the committee's discussions. "We need to go back internally and think about the advice in more detail. We have clearly heard that we need better [information on the] cardiovascular safety of diabetes drugs before approval. The FDA already has to decide whether the safety database of a drug in the approval application is sufficient to rule out harm, but the committee is now recommending that we should have more data to do this and that an unacceptably high risk needs to be ruled out before approval. This approach could also well be applied to drugs in other classes such as the [nonsteroidal anti-inflammatory drugs] NSAIDs."

Old Drugs Also to Be Scrutinized

Parks noted that the FDA also intends to reexamine data on diabetes drugs already on the market. "We will have to go back and look at each individual drug and the amount of evidence available to see if it is adequate or not to ensure cardiovascular safety. If not, we may have to ask for more data," she told the press conference.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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